The overall hypothesis of the proposed research is that NHR-49 senses changes in lipid environment and balances fatty acid oxidation and composition in an effort to maintain health and survival in response to nutrient availability. I propose to test this hypothesis through three specific aims: (1) to characterize the role of NHR-49 in a whole animal fasting response, (2) to determine the expression pattern and functional significance of NHR-49 regulated fasting response genes, and (3) to screen for factors that participate in the NHR-49-dependent signaling pathway in response to feeding and fasting. I will utilize the microscopic nematode, Caenorhabditis elegans (C.elegans), as the model organism in the proposed research. The genetic and anatomical simplicity of C.elegans combined with the conservation of many biological processes from worms to humans provides a powerful tool for mapping complex signaling networks. A combination of molecular biology and genetic techniques will be employed to map out the fasting response and to test the functional significance of each of the molecular players that participate in the metabolic adaptation to fasting. In addition to providing fuel to maintain health and survival in times of deprivation, fasting (experimentally implemented as dietary restriction) has proven a beneficial therapeutic intervention for increasing lifespan and alleviating symptoms of Huntington's, Parkinson's, epilepsy and diabetes. Delineation of the fasting response network and the role of NHR-49 in orchestrating this response will enable better understanding of these diseases as well as the potential for pharmacological intervention when fasting is not feasible or desirable. [unreadable] [unreadable] [unreadable]